Imides of 6-aminopenicillanic acid



United States Patent IMIDES 0F 6-AMINOPENICILLANIC ACID John R. E. Hoover, Gienside, and Bernard Loev,

Broomail, Pa., assignors to Smith Kline & French Laboratories, Philadelphia, Pa., a corporation of Pennsylvania No Drawing. Filed Feb. 7, 1963, Ser. No. 256,823

3 Claims. (Ci. 260-306.7)

This invention pertains to novel compounds possessing valuable chemotherapeutic activity and more specifically to a new class of compounds demonstrating important antimicrobial properties. 1

This application is an continuation-in-part of our copending application Serial No. 49,443, filed August 15, 1960, now abandoned.

More particularly, the compounds of this invention demonstrate not only a high level of antimicrobial activity against those micro-organisms showing a susceptibility to the known penicillin-type antibiotics, but also in addition, exhibit certain other properties which increase their value as chemotherapeutic agents. Specifically these compounds demonstrate a high resistance to the enzyme penicillinase, thus maintaining their antimicrobial activity for greater period of time than heretofore observed with many known antibiotics. This property of penicillinase resistance is further manifested by-both an improved stability to a purified preparation of this enzyme and more importantly by antimicrobial activity against certain micro-organisms which are presumably resistant to the known penicillins because of their ability to produce the enzyme penicillinase such as for example Bacillus cereus and penicillin-resistant variety of Staphylococcus aureus.

Our compounds are useful in the treatment of microbial infections many of which heretofore have been resistant to known penicillin therapy. The administration of these compounds to the infected host may be accomplished in any of the usual forms, such as for example, solutions, suspensions, creams, ointments, tablets, capsules, and the like, and are suitable for oral, injectable, or topical application, depending upon the nature of the particular infection.

The compounds of the present invention may be represented by the following structural formula:

0 II o wherein Z is a vincinally bound structure selected from the group consisting of'lower alkylene of from 2 to 6 carbon atoms, lower alkenylene of from 2 to 6 carbon atoms, lower cycloalkylene of from 4 to 6 carbon atoms, lower cycloalkenylene of from 4 to 6 carbon atoms, phenyl lower cycloalkylene of from 8 to 12 carbon atoms, phenyl lower cycloalkylene, phenylene, lower alkylphenylene, halogenophenylene, lower alkoxyphenylene, pyridinylene, piperidinylene, pyrrolylene, pyrrolidinylene and piperazinylene.

Also embraced within the scope of the present invention are the non-toxic pharmaceutically acceptable salts of the above carboxylic acid radical. The cations comprised in these salts and embraced by M include for example, the alkali metal ions as for instance the sodium ion, potassium ion, calcium ion as well as the organic amine cations, such as the lower alkyl ammonium groups (as for instance triethylammonium), procaine, l-ephenamine and the like.

The symbol Z is employed to represent certain carbon containing structures described herein which are bound to the two carboxy groups of the imido structure by two monovalent carbon-carbon bonds, one of each of said bonds arising from each of the two vincinal carbon atoms of the group represented by Z; Thus the imido structures of our invention embrace a five membered heterocyclic ring having a carbon skeleton similar to that found in a succinimide or maleimide:

The valence requirements of the four remaining bonds on the vicinal carbon atoms may be satisfied by the presence of four hydrogen atoms, i.e., succinimido; a double bond and two hydrogen atoms, i.e., maleimido; hydrogen and/or lower alkyl, e.g., ethylsuccinimido, e fi-dimethylsuccinimido; hydrogen and alkylene or alkenylene groups, e.g., 4-cyclohexene-1,2-dicarboxyimido, 3,4-dimethylcyclobutane-1,2-dicarboxyimido; phenylene, e.g., phthalimido; phenyl and hydrogen. e.g., 11,5 diphenylsuccinimido; or heterocyclic ring structures, e.g., pyridine-2,3- dicarboxyimido, piperidinylene; 3,4-dicarboxyimido and pyrrole-2,3-dicarboxyimido; and the substituted analogs of the above.

The compounds of our invention are thus imido derivatives of penicillanic acid and are prepared by treating 6- aminopenicillanic acid or a salt thereof with an appropriate carbo-(lower alkoxy)-imido compound such as a carboethoxyimido or carbomethoxyimido derivative. This reaction may be represented as follows, employing the carboethoxyimido derivative as representative:

While it is possible to form the desired imido compound according to certain other known methods heretofore employed for preparing imido compounds, as for example treatment with a diacyl halide, we have found that better yields can generally be obtained inthe imide formation and under less drastic conditions by employing the corresponding carbo-(lower alkoxy)-imido derivatives.

The required carbo-(lower alkoxy)-imido starting ma-. terial may be prepared, for example in the case of the preferred ethoxy compound, according to the following method. An appropriate a,;8-diearboxylic acid is converted to the acid anhydride according to known methods, as for instance by treatment with acetyl chloride. Treatment of this acid anhydride with ammonia then yields the imide which is converted to the carboethoxyimido reactant by treatment with ethylchloroformate.

The following examples will further serve to typify the nature of this invention. These examples, however, are representative only of embodiments of our invention and should not be construed as limiting the scope of this invention.

Example 1 A. To 204 g. (2 moles) of acetic anhydride are added 200 g. (1 mole) of 4-chlorophthalic acid. The mixture is heated until the solid dissolves and then heated for an additional 15 minutes. At the end of this time the reaction mixture is allowed to cool and the solid is then washed with a small amount of anhydrous ether which is free of ethanol and the washed solid then dried to yield 4-chlorophthalic anhydride.

B. There is added to 130 ml. (1.9 mole) of 28% aqueous ammonium solution, a total of 182 g. (1.0 mole) of 4-chlorophthalic anhydride. A large bore condenser is attached and the mixture is heated over an open flame for 1 /2 to 2 hours, or until all the water has evaporated, generally requiring a temperature in the range of about 300 C. The mixture comprising essentially of 4-chlorophthalimide is then covered and allowed to cool and employed in the next step without further purification.

C. To a stirred solution of 90 g. (0.5 mole) of 4-chlorophthalimide and 69 ml. (0.5 mole) of distilled triethylamine in 1 ml. of distilled dimethylformamide are slowly added at 5 C., 47.6 ml. (0.5 mole) of distilled ethylchloroformate. The addition rate is adjusted so that the temperature is maintained between 3 and 5 C. Upon completion of the addition, the reaction mixture is stirred at 0 C. for 30 minutes and then filtered. The filtrate so obtained is next poured into 3 l. of ice water With stirring and the solid which forms collected by filtration, washed with ether, dried and recrystallized twice from benzene-hexane to yield N-carboethoxy-4-chlorophthalimide.

D. To 30 ml. of water at room temperature are added 4.32 g. (0.02 mole) of 6-aminopenicillanic acid, 5.75 g. of sodium carbonate and 5.06 g. (0.02 mole) of N-carboethoxy-4-chlorophthalimide. The mixture is stirred for 20 minutes and then filtered. Acidification of the filtrate forms a solid material which is collected by filtration, dried and recrystallized from dimethylformamide to yield 6- (4-chlorophthalimido -penicillanic acid.

Example 2 Seventy-three grams of phthalimide are substituted for 4-chlorophthalimide in the procedure of Example 1, part C and upon execution of the procedure therein described followed by the procedure described in part D of Example 1, there is obtained the compound 6-phthalimidopenicillanic acid.

Example 3 3-ethylphthalic acid (174 g.) is employed in the procedure of Example 1 in place of 4-chlorophthalic acid. Upon completion of the steps therein described in parts A, B and C of this example then yields the compound N-carboethoxy-3-ethylphthalimide.

In a similar fashion by employing equivalent amounts of 4-methylphthalic acid, 3-t-butylphthalic acid, and

. 3-isopropyl-5-methylphthalic acid. There are respectively obtained the compounds N-carboethoxy-4-methylphthalimide, N-carboethoxy-3-butylphthalimide, and N-carboethoxy-3-isopropyl-S-methylphthalimide.

Subjection of the N-carboethoxy substituted phthalimides prepared herein to the procedure of Example 1, part D then yields respectively the compounds 6-(3- ethylphthalimido)-penicillanic acid, 6-(3-t-butylphthalimido)-penicillanic acid and 6-(3-isopropyl-5-methylphthalimido)-penicillanic acid.

In a similar fashion the following compounds are subjected in equivalent amounts to the procedures of Example 1 in its entirety: 3-bromophthalic acid, 4-iodophthalic acid, 4-ethoxyphthalic acid, 3'methoxyphthalic acid, 3-nitrophthalic acid, and 3-chloro-6-methoxyphthalic acid. There is thus respectively attained the compounds 6 (3-brornophthalirnidg)-penicillanic acid, 6-(4 iodophthalimido)-penicillanic acid, 6-(4-ethoxyphthalimido)- penicillanic acid, 6-(3-methoxyphthalimido)-penicillanic acid, 6-(3-nitrophthalimido)-penicillanic acid, and 6-(3- chloro-6-methoxyphthalimido)-penicillanic acid.

Example 4 There is substittued for 3-chlorophthalic acid, g. of cyclohexene-4,5-dicarboxylic acid. Upon completion of the steps therein described in Example 1, there is obtained the compound 6-(cyclohexene-4,S-dicarboxyimido)- penicillanic acid.

Similarly by employing equivalent amounts of 3-methylcyclohexene-4,5-dicarboxylic acid, there is obtained the compound 6-(3-methylcyclohexene-4,5-dicarboxyimido)- penicillanic acid.

Likewise there are employed the compounds hexane- 1,2-dicarboxylic acid, hexene-2,3-dicarboxylic acid and 1,3-cyclohexadiene-2,3-dicarboxylic acid. There are thus obtained the compounds 6-(hexane-l,2-dicarboxyimido)- penicillanic acid, 6-(hexene-2,3-dicarboxyimido)-penicillanic acid, and 6-(1,3cyclohexadiene-2,S-dicarboxyimido)-penicillanic acid.

By employing 1,4-cyclohexadiene-1,Z-dicarboxylic acid in the procedure of Example 1, there is obtained the compound 6-(1,4-cyclohexadiene-1,Z-dicarboxyimido)- penicillanic acid.

Example 5 Two hundred and thirteen grams of 3,4-dichlorocyclobutane-1,2-dicarboxylic acid are employed in the procedure of Example 1 and there is thus obtained upon execution of the recited steps the compound 6-(3,4-dichlorocyclobutane-l,Z-dicarboxyimido)-penicillanic acid.

In a similar fashion 3-methylcyclopentane-1,2-dicarboxylic acid is converted to the corresponding imido compound 3-methylcyclopentane-1,2-dicarboxyimido, this compound in turn converted to the N-carboethoxy derivative, and thence to the compound 6-(3-methylcyclopentane-1,2-dicarboxyimido)-penicillanic acid by following the procedure of Example 1.

Example 6 Forty-nine grams of succinimide is subjected to the reaction procedure described in Example 1, part C and there is thus obtained the compound N-carboethoxysuccinimide. Use of this compound in part D of Example 1 in substitution for N-carboethoxy-4-chlorophthalimide, then yields the compound 6-succinimidopenicillanic acid.

Use of methylsuccinic acid in the procedure of Example 1, parts A, B and C yields N-carboethoxymethylsuccinimide which may be employed in an analogous fashion as described in the present example according to the procedure of part D of Example 1 to yield the compound 6-methylsuccinimidopenicillanic acid.

Likewise a, 6-dibromosuccinic acid may be employed in these procedures to obtain the compound 6-(oc,fldibromosuccinimido)-penicillanic acid.

Example 7 Maleimide (48 g.) is treated with ethylchloroformate in triethylamine and dimethylformamide according to the procedure of Example 1, part C. There is thus obtained N-carboethoxymaleimide which when employed to treat 6-aminopenicillanic acid according to the method of Example 1, part D yields 6-maleimidopenicillanic acid.

Similarly citraconimide, prepared from citraconic acid according to the procedure of Example 1, parts A and B is converted to the N-carboethoxy derivative in an analogous fashion and this compound employed in the treatment of 6-arninopenicillanic acid to yield 6-citraconimidopenicillanic acid.

Phenylsuccinic acid (174 g.) is employed in the procedure of Example 1 to yield sequentially the compounds phenylsuccinic acid anhydride, phenylsuccinimide, N-carboethoxyphenylsuccinimide and 6-phenylsuccinimido' pcnicillani i Likewise by the use of benzylsuccinic acid, there are obtained according to this procedure the compound 6- benzylsuccinimidopenicillanic acid. In a similar fashion by the use of isopropylsuccinic acid and a-methyl-a-ethylsuccinic acid the execution of the steps of Example 1, there are obtained the compound 6-isopropylsuccinimidopenicillanic acid and 6-a-methyl-u-ethylsuccinimidopenicillanic acid.

Example 8 Employing piperidine-3,4dicarboxylic acid (160 g.) in the procedure of Example 1, parts A, B and C yields the compound piperidine-N-carboethoxy-3,4-dicarboxyimide. This reagent is employed to treat G-aminopenicillanic acid according to the procedure of Example 1, part D and yields 6-(piperidine-3,4-dicarboxyimido)-penicillanic acid.

In a similar fashion starting with 2,3-diphenylpiperazine-2,3-carboxylic acid, there is obtained the compound 6 (2,3 diphenylpiperazine-Z,3-dicarboxyimido)-penicillanic acid.

Similarly from 2-oxopyrrolidine-4,S-dicarboxylic acid and pyrrole-2,3-dicarboxylic acid, there are obtained according to the procedure of Example 1 the compound 6-(2-oxopyrrolidine-4,5-dicarboxyimido)-pencillanic acid and 6-(pyrrole-Z,3-dicarboxyimido)-penicillanic acid.

Use of pyridine-3,4-dicarboxylic acid in the procedure of Example 1 yields in a similar fashion after conversion to the imide and thence to the N-carboethoxy derivative thereof, the compound 6-(pyridine-3,4-dicarboxyimido) penicillanic acid.

Example 9 One gram of 6-(4-chlorophthalimido)-penicillanic acid is dissolved in excess amyl acetate and titrated with dilute sodium hydroxide to pH 8. The solution is then reduced in volume and the crystals which formed are collected by filtration to yield sodium 6-(4-chlorophthalimido)-penicillanate.

Example 10 One gram of 6-succinimidopenicillanic acid dissolved in excess amyl acetate and to the solution is added 10 g. of N-ethylpiperidine. The solution is stirred for 30 minutes and the crystals formed upon standing are collected by filtration and dried to yield the N-ethyl-piperidinium salt of 6-succinimidopenicillanic acid.

In a similar fashion by employing triethylamine, there is obtained 6-succinimidopenicillanic acid as the triethylamine salt.

6 What is claimed is: 1. A compound of the structural formula:

if C s OH f a M is selected from the group consisting of hydrogen, pharmaceutically acceptable nontoxic alkali metal cation-s and amine cations selected from the group consisting of triethylammonium, procaine, and l-ephenamine; and

Z is a vicinally bound structure selected from the group consisting of (loWer)-alkenylene of from 2 to 6 carbon atoms, lower cycloalkenylene of from 4 to 6 carbon atoms, (lower)-cycloalkylene of from 4 to 6 carbon atoms, phenyl-(lower)-alkylene, phenyl- (lower)-alkenylene of from 8 to 12 carbon atoms, mono-(lower)-alkylphenylene, monohalogenophenylene, mono (lower) alkoxyphenylene, pyridinylene, piperazinylene, piperidinylene, and pyrrolidinylene and pyrrolylene.

2. 6-maleimidopenicillanic acid.

3. 6-phenylsuccinimidopenicillanic acid.

References Cited by the Examiner UNITED STATES PATENTS 2,721,196 10/1955 Sheehan 260239.1 3,028,379 4/1962 Sheehan 260-239.1 3,082,204 3/1963 Perron 260239.1 3,173,911 3/1965 Hoover 260239.1

OTHER REFERENCES Burger: Medicinal Chemistry (2nd ed.), page 886, 1960.

Clarke et al.: The Chemistry of Penicillin, published by Princeton University Press, pages 92-95, 1949.

Nefkens: Nature, vol. 185, page 309 (January 1960).

Nefkens et a1.: Recueil des Travaux Chimique des Pays-Bas, vol. 79, No. 7, pages 688-698 (July 1960).

Sheehan et al.: Journal American Chemical Society, vol. 73, pages 4367-72 (1951).

Sheehan et al.: Journal American Chemical Society, vol. 73, pages 4373-75 (1951).

Sheehan et al.: Journal American Chemical Society, vol. 73, pages 4376- (1951).

Sheehan et al.: Journal American Chemical Society, vol. 75, pages 3292-93 (1953).

NICHOLAS S. RIZZO, Primary Examiner. 

1. A COMPOUND OF THE STRUCTURAL FORMULA: 